Biaryl ureas as potent and orally efficacious melanin concentrating hormone receptor 1 antagonists for the treatment of obesity

Article abstract of DOI:10.1021/jm0503852

Herein, we report a small molecule MCH-R1 antagonist which demonstrates oral efficacy in chronic rodent models. Substituted phenyl biaryl urea derivatives were synthesized and evaluated as MCH-R1 antagonists for the treatment of obesity. The structure-activity relationship studies in this series resulted in identification of urea 1 as a potent and selective MCH-R1 antagonist. Compound 1 exhibited oral efficacy in chronic (28 d) rodent models at 3-30 mpk showing significant reduction in food intake and weight gain relative to controls.

Full text of DOI:10.1021/jm0503852

4746
J. Med. Chem. 2005, 48, 4746-4749
Letters
Biaryl Ureas as Potent and Orally
Efficacious Melanin Concentrating
Hormone Receptor 1 Antagonists for the
Treatment of Obesity
Anandan Palani,* Sherry Shapiro, Mark D. McBriar,
John W. Clader, William J. Greenlee, Brian Spar,
Timothy J. Kowalski, Constance Farley, John Cook,
Margaret van Heek, Blair Weig, Kim O’Neill,
Michael Graziano, and Brian Hawes
Schering-Plough Research Institute, 2015 Galloping Hill
Road, Kenilworth, New Jersey 07033
Received April 22, 2005
Abstract: Herein, we report a small molecule MCH-R1
antagonist which demonstrates oral efficacy in chronic rodent
models. Substituted phenyl biaryl urea derivatives were
synthesized and evaluated as MCH-R1 antagonists for the
treatment of obesity. The structure-activity relationship
studies in this series resulted in identification of urea 1 as a
potent and selective MCH-R1 antagonist. Compound 1 exhib-
ited oral efficacy in chronic (28 d) rodent models at 3-30 mpk
showing significant reduction in food intake and weight gain
relative to controls.
Figure 1. Biaryl urea containing MCH-R1 antagonists.
Scheme 1a
Melanin concentrating hormone (MCH) is a 19-amino
acid cyclic peptide found in the brains of all vertebrate
species which serves as an important mediator in the
regulation of food intake and energy balance.1,2 An icv
injection of MCH in rats stimulates food intake,3 and
chronic administration leads to increased body weight.4
Mice overexpressing the MCH gene are hyperphagic,
mildly obese, hyperglycemic, and insulin resistant.5 In
contrast, mice that lack the gene encoding MCH are
lean and hypophagic.6 These observations suggest that
MCH antagonists could be useful for the treatment of
obesity. Several companies have published their efforts
in identification of small molecule MCH receptor
antagonists.7-9 We report herein our initial SAR studies
which resulted in discovery of biaryl ureas as potent and
selective MCH-R1 antagonists as exemplified by com-
pound 1 (Figure 1).
a Reagents and conditions: (a) 1-tert-butoxycarbonyl-4-piperi-
done, Ti(O-i-Pr)4, 18 h, then NaCNBH3, MeOH, 50%; (b) TFA, rt,
CH2Cl2, 90%; (c) (R2)2CO or R2CHO, NaBH(OAc)3, AcOH, CH2Cl2
50-90%; (d) R1-aryl boronic acid, Na2CO3, Pd(PPh3)4, toluene:
EtOH:H2O or PdCl2(PPh3)2, Na2CO3, DME:H2O, 30-80%; (e)
ArNCO, Et3N, CH2Cl2, 75-100%.
Our initial SAR optimization of the original screening
hit from our compound collection resulted in identifica-
tion of urea 2.10 This compound is a potent but nonse-
lective MCH-R1 antagonist (Ki ) 3.9 nM) which also
antagonized the muscarinic M2 receptor (M2 Ki ) 532
nM). Truncation of the carbon chain between the biaryl
and urea functionalities provided compound 3 which
exhibited an improvement in selectivity versus the M2
receptor while retaining MCH-R1 potency. Replacement
of the urea functionality in compound 3 with an amide
or sulfonamide resulted in complete loss of activity. Also,
N-methylation of the urea resulted in a significant drop
in affinity, confirming the importance of the urea N-H
and its possible hydrogen bonding interaction with the
receptor. In this paper, we describe SAR derived from
varying substituents at the biaryl and urea and replace-
ment of the piperidine ring with an amino ethyl side
chain.
The synthesis of biaryl anilino-piperidine ureas is
outlined in Scheme 1. Reductive amination of 1-tert-
butoxycarbonyl-4-piperidone with p-bromoaniline af-
forded compound 5. Carbamate removal with trifluoro-
acetic acid and reductive amination of the resultant
amine with the various aldehydes or ketones under
standard conditions gave the desired product 6. Pal-
ladium-catalyzed Suzuki coupling followed by treating
7 with aryl isocyanates afforded the desired biaryl urea
products 3 and 8-20. Alternatively, palladium-cata-
* To whom correspondence should be addressed. Tel: 908-740-7158.
Fax: 908-740-7152. E-mail: anandan.palani@spcorp.com.
10.1021/jm0503852 CCC: $30.25 © 2005 American Chemical Society
Published on Web 06/24/2005

Letters
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15 4747
Scheme 2a
Table 2. MCH Receptor Binding for Biaryl Aminoethyl Urea
Analogues
rat PK
(10 mg/kg,
h-MCH-R1 h-MCH-R1 po)c AUC0-6h
a Reagents and conditions: (a) 3-cyanophenyl boronic acid,
Na2CO3, Pd(dppf)Cl2, DME:H2O, 66% (b) ClCH2CHO, NaCNBH3,
HCl, MeOH, 67%; (c) amine, K2CO3, NaI, CH3CN, 99%; (d) ArNCO,
Et3N, CH2Cl2, 75-100%.
no.
R2
R3
Ki (nM)a
Kb (nM)b
(h ng/mL)
23 NMe2
24 NMe2
25 NHMe
26 NMe2
3, 5-diCl
3-Cl,4-F
3-Cl,4-F
19 ( 8
3.3 ( 0.2
6.0 ( 3.5
3.1 ( 0.7
6.2 ( 1.7
1950
3-F,4-CF3 6.0 ( 0.4
3-F,4-CF3 5.6 ( 1.0
3-F,4-CF3 8.2 ( 0.6
4800
967
542
Table 1. MCH Receptor Binding for Biaryl Piperidine Urea
Modifications
27 pyrrolidinyl
28 4-methyl-
piperazinyl
29 (S)-3-OH-
3-F,4-CF3 7.3 ( 0.5
3-F,4-CF3 8.9 ( 1.1
1449
5470
pyrrolidinyl
(R)-3-OH-
pyrrolidinyl
1
2.0 ( 0.2
8.0 ( 0.1
30
31
32
“
“
“
3,5-diCl
3-Cl,4-F
11 ( 3
7.1 ( 1.5
3-CF3,4-F 1.8 ( 0.6
1850
1080
2790
a Mean values (n ) 3) ( SEM. h-MCH-R1 denotes human
MCH-R1. b Inhibition of MCH-mediated Ca2+ influx into cells
expressing hMCH-R1 via FLIPR assay. Affinity at h-MCH-R2 >3
µM for all compounds. c See ref 11 for procedure
h-MCH-R1 h-MCH-R1
compd
R1
R2
R3
Ki (nM)a
Kb (nM)b
3
m-CN
cyclopentyl
3,5-diCl
3,5-diCl
3,5-diCl
3,5-diCl
H
2.6 ( 0.4 5.5 ( 1.4
20 ( 1
over the ortho and para derivatives. Furthermore, the
cyano group was found to be the best meta substituent,
while potency was also observed for 3-chloro and 3-tri-
fluromethoxy groups. With m-cyano determined as an
optimal group at the distal aryl ring, we next studied
the influence of phenyl urea substitution (R3) and alkyl
groups (R2).
The unsubstituted phenyl urea 11 was several fold
less potent than 3,5-dichloro phenyl compound 3. In
general, dihalogenated aryl ureas were slightly better
than monohalogenated aryls in terms of MCH-R1 bind-
ing affinity. As illustrated by compounds 13 and 14, the
nonhalogenated electron-donating substituents, such as
3-methoxy and 4-methoxy, exhibited a significant loss
of potency. The 3-chloro-4-fluorophenyl and 3-trifluoro-
methyl-4-fluoro substitution (15 and 16) were some of
the best among the several disubstituted ureas pre-
pared. One possible explanation for this increased
affinity could be due to enhancement of urea N-H
hydrogen bonding interaction with the receptor by
electron-withdrawing groups.
Having defined the SAR of aryl substituents, we next
explored the influence of terminal alkyl groups (R2) on
the piperidine. The sulfonamide 19 and amide 20 were
much less active, indicating the importance of main-
taining basicity at the nitrogen atom. Compound 17,
where R2 ) Et, showed potency similar to the cyclopen-
tyl-substituted compounds.
To further investigate the binding mode and the
importance of the piperidine ring, we explored the
possibility of replacement of the ring with aminoethyl,
aminopropyl, and aminobutyl linkers. The aminoethyl
linker was optimal for MCH-R1 binding. Table 2 sum-
marizes the SAR of the MCH-R1 binding activities along
8
m-OCF3 cyclopentyl
9
m-CF3
m-Cl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
cyclopentyl
Et
197 ( 5
10
11
12
13
14
15
16
17
18
12.5 ( 0.9
233 ( 10
m-CN
m-CN
m-CN
m-CN
m-CN
m-CN
m-CN
m-CN
3-Cl
5.8 ( 0.4
3-OCH3
4-OCH3
3-Cl,4-F
4-F,3-CF3
4-F,3-CF3
4-F,3-CF3
98 ( 2
139 ( 7
1.6 ( 0.1 1.3 ( 0.5
1.9 ( 0.5
7.1 ( 2.0
4.0 ( 0.8
cyclopropyl-
methyl
-
19
20
m-CN
m-CN
EtSO2
4-F,3-CF3 166 ( 14
i-propyl-(CO)- 4-F,3-CF3 374 ( 7
a Mean values (n ) 3) ( SEM. h-MCH-R1 denotes human MCH-
R1. b Inhibition of MCH-mediated Ca2+ influx into cells expressing
hMCH-R1 via FLIPR assay. Affinity at h-MCH-R2 >3 µM for all
compounds.
lyzed Suzuki coupling reactions could be carried out
prior to carbamate removal and reductive amination.
The synthesis of biaryl anilino-aminoethyl ureas
proceeded via Scheme 2. Suzuki coupling between
p-bromoaniline and 3-cyanophenyl boronic acid afforded
compound 21. Reductive alkylation of the resulting
aniline 21 with chloroacetaldehyde, followed by chloride
displacement with various amines, provided compound
22. The previously described isocyanate formation af-
forded the final products.
Table 1 shows the MCH-R1 activities of several
representative compounds containing modifications at
urea phenyl, biaryl, and alkyl groups attached to the
piperidine ring. For our initial SAR we fixed the phenyl
urea as 3,5-dichlorophenyl, and R2 as cyclopentyl, and
introduced varied substituents at the distal biaryl ring.
We noted that for these series of compounds, meta
substitution at the distal ring of the biaryl was preferred

4748 Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15
Letters
Figure 3. Effect of compound 1 (1, 3, and 10 mg/kg, po for 28
days) on the body composition of DIO rats. *(p < 0.05 vs
baseline, paired t-test).
Figure 2. Effect of compound 1 (1, 3, and 10 mg/kg po for 28
days) on the body weight of DIO rats. All values are means (
SEM; n ) 11-12/group.
weight gain (1.2 ( 10.6 g, and 2.2 ( 4.0 g weight gain
at 3 and 10 mg/kg 1, respectively, relative to 25.2 ( 4.6
g weight gain with control; p < 0.05. DEXA scanning
revealed that the decrease in body weight gain at the
10 mg/kg dose was associated with a selective decrease
in fat mass (Figure 3). Animals treated at a 1 mg/kg
dosage did not show any significant change in body
weight or food intake relative to control. Importantly,
compound 1 did not cause taste aversion or place
preference at a dose of 3 and 10 mg/kg.
Compound 1 showed excellent in vitro and moderate
in vivo activity; however, further studies with this
compound were discontinued due to the presence of a
highly mutagenic, Ames positive biarylaniline subunit.15
Although the compound 1 is nonmutagenic, and there
is no evidence to suggest that biarylaniline 21 is
generated in vivo, the risk of possible exposure to this
highly mutagenic biarylaniline intermediate at any
stage in the development of the series was considered
unacceptable. Our research focus was then shifted to
identify a nonmutagenic functional group exhibiting the
otherwise promising profile of the biaryl urea.13 The
other strategies followed to address the mutagenicity
issue will be reported in due course.
with plasma levels from rat PK studies of the amino-
ethyl biaryl urea analogues. The SAR on the urea and
biaryl portion of the molecules tracked similarly to that
of the piperidine series. Compound 24 exhibited excel-
lent potency and also showed reasonable oral plasma
levels in rats. Metabolite identification studies indicated
that compound 24 underwent demethylation in vivo to
provide compound 25. The metabolite, and to some
extent the parent compound, exhibited potent 5-HT
reuptake transporter inhibition (5-HT Ki ) 27 ( 2 nM
for compound 25 and 1076 ( 187 nM for 24). At this
point, this was a significant issue because serotonergic
modulation can also play a significant role in the
regulation of food consumption and weight loss.12 There-
fore, our goal became to eliminate serotonin transporter
affinity in order to understand the effects of a pure
MCH-R1 antagonist as an antiobesity agent. Substitu-
tion at the aryl urea, and alkyl group alterations at the
amine terminus, did not reduce 5-HT activity. However,
the pyrrolidine and piperazine analogues 1 (5-HT Ki >
1 uM) and 28 (5-HT Ki >1 uM) showed promising
selectivity in addition to maintaining good MCH-R1
activity. Further SAR studies of pyrrolidine analogues
resulted in the identification of 1, which showed an
excellent profile in terms of MCH-R1 affinity and
selectivity over other receptors such as NPY, 5-HT, M2,
MCH-R2, and 5-HT transporter inhibition (>1 µM)
along with oral rat plasma levels, including good brain
levels (579 ng/g) at 6 h.
Oral administration of 1 to 24 h fasted diet-induced
obese (DIO) mice (30 mg/kg) significantly reduced food
intake relative to vehicle control by 16 ( 6%, 17 ( 6%
and 14 ( 5% at 4, 6, and 24 h postdose, respectively (p
< 0.05, t-test). Using an ex vivo binding assay13 as a
surrogate measure of receptor occupancy, compound 1
exhibited 85 ( 3% and 56 ( 3% inhibition of MCH
binding to MCH-R1 in mouse brain slices at 6 and 24 h
postdose, respectively. Moreover, compounds with low
ex vivo binding lacked efficacy, indicating that changes
in food intake are likely due to MCH-R1 antagonism.
When orally administered to DIO rats for 28 d, com-
pound 1 (1, 3, or 10 mg/kg) produced a dose-dependent
decrease in food intake [F3,45 ) 8.83; p ) 0.0001] and
body weight gain [F3,45 ) 3.74; p ) 0.0175] throughout
the duration of the treatment (Figure 2).14 Specifically,
1 significantly reduced cumulative food intake by 16.9
( 2.1% and 13.2 ( 1.6% (3 and 10 mg/kg 1, respectively;
p < 0.05) relative to control rats while suppressing body
Acknowledgment. We thank Dr. Catherine Strader
and Dr. John Piwinski for helpful discussions, support,
and encouragement, Dr. Jesse Wong and Dr. Mark
Liang for scale-up of intermediates, and Dr. Kathleen
Cox for pharmacokinetic studies.
Note Added after ASAP Publication. In the ver-
sion of the manuscript posted June 24, 2005, compounds
3, 8-20 in Scheme 1 were drawn incorrectly. The
corrected structures are presented in the version posted
June 29, 2005.
Supporting Information Available: Experimental pro-
cedures and characterization data for compounds 1, 3, 8-20,
and 23-32. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
(1) Saito, Y.; Nothacker, H.-P.; Civelli, O. Melanin-concentrating
hormone receptor: an orphan receptor fits the key. Trends
Endocrinol. Metab. 2000, 11, 299-303.
(2) Schwartz, M. W.; Woods, S. C.; Porte, D., Jr.; Selley, R. J.;
Baskin, D. G. Central nervous system control of food intake.
Nature 2000, 404, 661-671.
(3) Della-Zuana, O.; Presse, F.; Ortola, C.; Duhault, J.; Nahon, J.
L.; Levens, N. Acute and chronic administration of melanin-
concentrating hormone enhances food intake and body weight
in Wistar and Sprague-Dawley rats. Int. J. Obesity 2002, 26,
1289-1295.

Letters
(4) Gomori, A.; Ishihara, A.; Ito, M.; Mashiko, S.; Matsushita, H.;
Journal of Medicinal Chemistry, 2005, Vol. 48, No. 15 4749
nin concentrating hormone receptor antagonists. WO 2002/
076947.
(11) Cox, K. A.; Dunn-Meynell, K.; Korfmacher, W. A.; Broske, L.;
Nomeir, A. A.; Lin, C. C.; Cayen, M. N.; Barr, W. H. Drug
Discovery Today 1999, 4(5), 232-237.
(12) (a) Blundell J. E.; Hill A. J.; Int. J. Dexfenfluramine and appetite
in humans Relat. Metab. Disord. 1992, 16: Suppl.3: S51-S59.
(b) Blundell J. E. Serotonin and appetite Neuropharmacology
1984, 12B, 1537-1551.
(13) McBriar, M. D.; Guzik, H.; Xu, R.; Paruchova, J.; Li, S.; Palani,
A.; Clader, J. W.; Greenlee, W. J.; Hawes, B. E.; Kowalski, T.;
O’Neil, K.; Spar, B.; Weig, B. Discovery of bicycloalkyl urea
melanin concentrating hormone receptor antagonists: orally
efficacious antiobesity therapeutics J. Med. Chem. 2005, 48,
2274-2277.
Yumoto, M.; Ito, M.; Tanaka, T.; Tokita, S.; Moriya, M.; Iwaasa,
H.; Kanatani, A. Chronic intracerebroventricular infusion of
MCH causes obesity in mice. Am. J. Physiol. Endocrinol. Metab.
2003, 284, E583-E588.
(5) Ludwig, D. S.; Tritos, N. A.; Mastaitis, J. W.; Kulkarni, R.;
kokkotou, E.; Elmquist, J.; Lowell, B.; Flier, J. S.; Maratos-Flier,
E. Melanin-concentrating hormone overexpression in transgenic
mice leads to obesity and insulin resistance J. Clin. Invest. 2001,
107, 379-386.
(6) Shimada, M.; Tritos, N. A.; Lowell, B. B.; Flier, J. S.; Maratos-
Flier, E. Mice lacking melanin-concentrating hormone are
hypophagic and lean. Nature 1998, 396, 670-674.
(7) Kowalski, T. J.; McBriar, M. D. Therapeutic potential of melanin
concentrating hormone receptor antagonists for the treatment
of obesity. Expert Opin. Invest. Drugs 2004, 13, 1113-1122.
(8) Takekawa, S.; Asami, A.; Ishihara, Y.; Terauchi, J.; Kato, K.;
Shimomura, Y.; Mori, M.; Murakoshi, M.; Kato, K.; Suzuki, N.;
Nishimura, O.; Fujino, M. T-226296: A novel, orally active and
selective melanin concentrating hormone receptor antagonist.
Eur. J. Pharmacol. 2002, 438, 129-135.
(14) Repeated measures ANOVA was used to compare cumulative
food intake and body weight gain measures across time in rat
28d study. Where significant differences by ANOVA (p < 0.05)
were found, posthoc analyses were carried out using Fishers
PLSD.
(15) (a) Dang, L. N.; McQueen, C. A. Mutagenicity of 4-aminobiphenyl
and 4-acetylaminobiphenyl in salmonella typhimurium strains
expressing different levels of N-acetyltransferase Toxicol. Appl.
Pharmacol. 1999, 159, 77-82. (b) Nohara, M.; Hirayama, T.;
Fujioka, Y.; Ozasa, S.; Ibuki, E.; Fukui, S. Relationship between
mutagenic potency in salmonella typhimurium and chemical
structure of amino- and nitro substituted biphenyls. Mutation
Res. 1985, 149, 9-15.
(9) Souers, A. J.; Gao, J.; Brune, M.; Bush, E.; Wodka, D.; Vasude-
van, A.; Judd, A. S.; Mulhern, M.; Brodjian, S.; Dayton, B.;
Shapiro, R.; Hernandez, L. E.; Marsh, K. C.; Sham, H. L.; Collins,
C. A.; Kym, P. R. Identification of 2-(4-benzyloxyphenyl)-N-[1-
(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide, an orally ef-
ficacious melanin-concentrating hormone receptor-1 antagonist
for the treatment of obesity. J. Med. Chem. 2005, 48, 1318-
1321.
(10) Clader, J. W.; Josien, H, B. Palani. A.; Chan, T.-Y. Preparation
of N-[biaryl(piperidinyl)ethyl]-N′-arylureas and analogs as mela-
JM0503852